When certain protein has a functional site that adversely affects human bodies, it is important to design a ligand that stably bonds with the functional site of the protein in drug discovery for the protein serving as a target. The functional site of the protein is blocked by stabling bonding the ligand to the protein. As a result, the adverse effect of the protein to human bodies can be prevented.
In order to judge whether a bond between the protein and the ligand is stable or not, typically, a technique for highly accurately determining interaction energy between the protein and the ligand using a method based on quantum mechanics (QM) has been commonly used (see, for example, Kazuo Kitaura, Eiji Ikeo, Toshio Asada, Tatsuya Nakano, Masami Uebayasi, Chemical Physics Letters, 313, (1999), 701-706).
The method based on QM has a problem that a calculation time exponentially increases, as the number of atoms of a calculation target increases. The number of atoms for only a complex of the protein and the ligand may be a few thousands, but the number of atoms may be a several tens thousands when water molecules present around the complex are included. Accordingly, there is a problem in a calculation time when a QM calculation including water molecules is performed.
In order to achieve efficiency of the interaction energy calculation, a technique for approximating water molecules with a solvent as a uniform continuum has been proposed (see, for example, D. G. Fedorov, K. Kitaura, H. Li, J. H. Jensen, M. S. Gordon, J. Comput. Chem. 27, 976-985 (2006)). In the proposed technique, the number of atoms does not increase, and therefore an exponential increase of the calculation time can be avoided.
In the proposed technique, however, the continuum approximation is destroyed when a complex of the protein and the ligand is bonded to water with hydrogen bonds. In order to determine appropriate interaction energy, therefore, water is expressly considered, which is not efficient in terms of a calculation time.
There is a case where a drug candidate molecule having large interaction energy with a target molecule, such as protein, is estimated among a plurality of drug candidate molecules (ligand). In this case, each interaction energy between the target molecule and each of the drug candidate molecules is determined in the presence of water molecules. Then, the obtained values of the interaction energy are compared. When the values of the interaction energy are compared, reliability of a relative relationship between the values of the obtained interaction energy is more important than absolute values of the interaction energy. Therefore, there is a need for efficiently calculating interaction energy having a relative relationship of high reliability. However, the above-described proposed techniques do not sufficiently meet such a need.